MCF7 time-series upon RITA treatment.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE13291 | GEO | 2009/05/12
SECONDARY ACCESSION(S): PRJNA109617
REPOSITORIES: GEO
Similar Datasets
Project description:Targeting “oncogene addiction” is a promising strategy for anti-cancer therapy. Here, we report a potent inhibition of crucial oncogenes by p53 upon reactivation with small molecule RITA in vitro and in vivo. RITA-activated p53 unleashes transcriptional repression of anti-apoptotic proteins Mcl-1, Bcl-2, MAP4, and survivin, blocks Akt pathway on several levels and downregulates c-Myc, cyclin E and B-catenin. p53 ablates c-Myc expression via several mechanisms at transcriptional and posttranscriptional level. We show that transrepression of oncogenes correlated with higher level of p53 bound to chromatin-bound p53 than transactivation of pro-apoptotic targets. Inhibition of oncogenes by p53 reduces the cell’s ability to buffer pro-apoptotic signals and elicits robust apoptosis. Our study highlights the role of transcriptional repression for p53-mediated tumor suppression. Experiment Overall Design: Breast carcinoma cell-line MCF7 was treated with the small-molecule p53 activator RITA for 2h, 8h, 16h and 24h.
2009-05-15 | E-GEOD-13291 | biostudies-arrayexpress
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Project description:The tumor suppressor p53 can induce various biological responses. Yet it is not clear whether it is p53 in vivo promoter selectivity that triggers different transcription programs leading to different outcomes. Our analysis of genome-wide chromatin occupancy by p53 using ChIP-seq (deposited in Sequence Read Archive database as SRP007261) revealed “p53 default program”, i.e. the pattern of major p53-bound sites that is similar upon p53 activation by nutlin3a, RITA or 5-FU in breast cancer cells, despite different biological outcomes triggered by these compounds. Parallel analysis of gene expression allowed identification of 280 previously unknown p53 target genes, including p53-repressed AURKA. The consensus p53 binding motif was present more frequently in p53-induced, than in repressed targets, indicating different mechanisms of gene activation versus repression. We identified several possible cofactors of p53, and found that STAT3 antagonised p53-mediated repression of a subset of genes, including AURKA. Finally, we showed that the expression of the novel p53 targets correlates with p53 status and survival in breast cancer patients. We used microarrays to detail the global programme of gene expression changed upon nutlin3a treatment and knocking-down of STAT3 transcription program
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Project description:Since its discovery as a tumour suppressor some fifteen years ago, the transcription factor p53 has attracted paramount attention for its role as “the guardian of the genome”. TP53 mutations occur so frequently in cancer, regardless of patient age or tumour type, that they appear to be part of the life history of at least 50% of human tumours. In most tumours that retain wild-type p53, its function is inactivated due to deregulated HDM2, a protein which binds to p53 and which can inhibit the transcriptional activity of p53 and induce its degradation. RITA is a low-molecular-weight compound which addresses the second group of tumours retaining functionally reactive wt p53. It was found in a screening of the National Cancer Institute (NCI) library of low-molecular-weight compounds based on its ability to selectively kill wtp53-containing cells. RITA binds directly to p53 and diplaces its main destructor Mdm2, as well as inducing a shift in the conformation of p53. This is in contrast to the wtp53-reactivating compound Nutlin3a, which targets Mdm2, inhibiting its ability to degrade p53. Using microarray technology we have explored the effect of RITA on the transcriptome of isogenic cell-lines with knocked-out (KO) or intact (WT) TP53. While the effects on KO cells are below detection limit, the effects on WT cells are profound. The known p53 targets induced are predominately apoptotic, in contrast to the genes affected by Nutlin3a, which are exclusively growth-arrest genes. Keywords: Antitumor agent
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Project description:C-MYC (henceforth MYC) is one of the most frequently overexpressed oncogenes in human cancer and even modestly deregulated MYC expression can initiate ectopic proliferation in many post-mitotic, terminally differentiated cell types in vivo. Metazoan organisms have consequently evolved a number of mechanisms to counteract MYC's oncogenic potential, of which apoptosis is arguably the best understood. However, the mechanisms through which MYC induces apoptosis remains controversial, with some studies implicating p19ARF-mediated stabilization of p53, followed by induction of pro-apoptotic BH3 family member NOXA and PUMA, while others argue for more direct regulation of BH3 proteins, especially BIM. The debate likely stems from the use of different experimental systems, modes of perturbation, and quite possibly different levels of MYC expression. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used tumoricidal chemotherapeutic, Doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.
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